tbuckley/cabot-search huggingface dataset:
Loss of GM-CSF-dependent instruction of alveolar macrophages in COVID-19 provides a rationale for inhaled GM-CSF treatment
Authors: Cedric Bosteels, Karel F.A. Van Damme, Elisabeth De Leeuw, Jozefien Declercq, Bastiaan Maes, Victor Bosteels, Levi Hoste, Leslie Naesens, Nincy Debeuf, Julie Deckers, Basiel Cole, Marion Pardons, Daniela Weiskopf, Alessandro Sette, Yannick Vande Weygaerde, Thomas Malfait, Stefaan J. Vandecasteele, Ingel K. Demedts, Hans Slabbynck, Sabine Allard, Pieter Depuydt, Eva Van Braeckel, Jozefien De Clercq, Liesbet Martens, Sam Dupont, Ruth Seurinck, Niels Vandamme, Filomeen Haerynck, Debasish F. Roychowdhury, Linos Vandekerckhove, Martin Guilliams, Simon J. Tavernier, Bart N. Lambrecht
Journal: Cell Reports Medicine (2022)

GM-CSF promotes myelopoiesis and inflammation, and GM-CSF blockade is being evaluated as a treatment for COVID-19-associated hyperinflammation. Alveolar GM-CSF is, however, required for monocytes to differentiate into alveolar macrophages (AMs) that control alveolar homeostasis. By mapping cross-species AM development to clinical lung samples, we discovered that COVID-19 is marked by defective GM-CSF-dependent AM instruction and accumulation of pro-inflammatory macrophages. In a multi-center, open-label RCT in 81 non-ventilated COVID-19 patients with respiratory failure, we found that inhalation of rhu-GM-CSF did not improve mean oxygenation parameters compared with standard treatment. However, more patients on GM-CSF had a clinical response, and GM-CSF inhalation induced higher numbers of virus-specific CD8 effector lymphocytes and class-switched B cells, without exacerbating systemic hyperinflammation. This translational proof-of-concept study provides a rationale for further testing of inhaled GM-CSF as a non-invasive treatment to improve alveolar gas exchange and simultaneously boost antiviral immunity in COVID-19. This study is registered at ClinicalTrials.gov (NCT04326920) and EudraCT (2020-001254-22).
Gene set predictor for post-treatment Lyme disease
Authors: Daniel J.B. Clarke, Alison W. Rebman, Jinshui Fan, Mark J. Soloski, John N. Aucott, Avi Ma’ayan
Journal: Cell Reports Medicine (2022)

Lyme disease (LD) is tick-borne disease whose post-treatment sequelae are not well understood. For this study, we enrolled 152 individuals with symptoms of post-treatment LD (PTLD) to profile their peripheral blood mononuclear cells (PBMCs) with RNA sequencing (RNA-seq). Combined with RNA-seq data from 72 individuals with acute LD and 44 uninfected controls, we investigated differences in differential gene expression. We observe that most individuals with PTLD have an inflammatory signature that is distinguished from the acute LD group. By distilling gene sets from this study with gene sets from other sources, we identify a subset of genes that are highly expressed in the cohorts but are not already established as biomarkers for inflammatory response or other viral or bacterial infections. We further reduce this gene set by feature importance to establish an mRNA biomarker set capable of distinguishing healthy individuals from those with acute LD or PTLD as a candidate for translation into an LD diagnostic.
Blood-Oxygen-Level Dependent (BOLD) T2-Mapping Reflects Invasively Measured Central Venous Oxygen Saturation in Cardiovascular Patients
Authors: Alessio Alogna, Alessandro Faragli, Carolin Kolp, Patrick Doeblin, Radu Tanacli, Giada Confortola, Jens Oetvoes, Simone Perna, Christian Stehning, Eike Nagel, Burkert M. Pieske, Heiner Post, Sebastian Kelle
Journal: JACC. Cardiovascular imaging (2022)
Hyperpolarized Metabolic and Parametric CMR Imaging of Longitudinal Metabolic-Structural Changes in Experimental Chronic Infarction
Authors: Maximilian Fuetterer, Julia Traechtler, Julia Busch, Sophie Marie Peereboom, Andreas Dounas, Robert Manka, Miriam Weisskopf, Nikola Cesarovic, Christian Torben Stoeck, Sebastian Kozerke
Journal: JACC. Cardiovascular imaging (2022)

Prolonged ischemia and myocardial infarction are followed by a series of dynamic processes that determine the fate of the affected myocardium toward recovery or necrosis. Metabolic adaptions are considered to play a vital role in the recovery of salvageable myocardium in the context of stunned and hibernating myocardium. The potential of hyperpolarized pyruvate cardiac magnetic resonance (CMR) alongside functional and parametric CMR as a tool to study the complex metabolic-structural interplay in a longitudinal study of chronic myocardial infarction in an experimental pig model is investigated. Metabolic imaging using hyperpolarized [1-13C] pyruvate and proton-based CMR including cine, T1/T2 relaxometry, dynamic contrast-enhanced, and late gadolinium enhanced imaging were performed on clinical 3.0-T and 1.5-T MR systems before infarction and at 6 days and 5 and 9 weeks postinfarction in a longitudinal study design. Chronic myocardial infarction in pigs was induced using catheter-based occlusion and compared with healthy controls. Metabolic image data revealed temporarily elevated lactate-to-bicarbonate ratios at day 6 in the infarcted relative to remote myocardium. The temporal changes of lactate-to-bicarbonate ratios were found to correlate with changes in T2 and impaired local contractility. Assessment of pyruvate dehydrogenase flux via the hyperpolarized [13C] bicarbonate signal revealed recovery of aerobic cellular respiration in the hibernating myocardium, which correlated with recovery of local radial strain. This study demonstrates the potential of hyperpolarized CMR to longitudinally detect metabolic changes after cardiac infarction over days to weeks. Viable myocardium in the area at risk was identified based on restored pyruvate dehydrogenase flux.
Durability of COVID-19 vaccine induced T-cell mediated immune responses measured using the QuantiFERON SARS-CoV-2 assay
Authors: F. Stieber, N. Allen, K. Carpenter, P. Hu, R. Alagna, S. Rao, D. Manissero, J. Howard, V. Nikolayevskyy
Journal: Pulmonology (2022)
Longitudinal Right Ventricular Systolic Function Changes in Breast Cancer Patients Treated With Cardiotoxic Cancer Therapy
Authors: Biniyam G. Demissei, Natasha A. Vedage, Rebecca A. Hubbard, Amanda M. Smith, Jade Chung, Bénédicte Lefebvre, Kelly D. Getz, Paaladinesh Thavendiranathan, Hari K. Narayan, Bonnie Ky
Journal: JACC CardioOncology (2022)
Maternal vitamin D status modifies the effects of early life tobacco exposure on child lung function
Authors: Hanna M. Knihtilä, Mengna Huang, Nicole Prince, Benjamin J. Stubbs, Vincent J. Carey, Nancy Laranjo, Hooman Mirzakhani, Robert S. Zeiger, Leonard B. Bacharier, George T. O’Connor, Augusto A. Litonjua, Scott T. Weiss, Jessica Lasky-Su
Journal: Journal of Allergy and Clinical Immunology (2022)
Increased risk of thrombosis in JAK2 V617F-positive patients with primary myelofibrosis and interaction of the mutation with the IPSS score
Authors: Tiziano Barbui, Arianna Ghirardi, Alessandra Carobbio, Arianna Masciulli, Greta Carioli, Alessandro Rambaldi, Maria Chiara Finazzi, Marta Bellini, Elisa Rumi, Daniele Vanni, Oscar Borsani, Francesco Passamonti, Barbara Mora, Marco Brociner, Paola Guglielmelli, Chiara Paoli, Alberto Alvarez-Larran, Ana Triguero, Marta Garrote, Helna Pettersson, Björn Andréasson, Giovanni Barosi, Alessandro Maria Vannucchi
Journal: Blood Cancer Journal (2022)
A flexible two-photon fiberscope for fast activity imaging and precise optogenetic photostimulation of neurons in freely moving mice
Authors: Nicolò Accanto, François G.C. Blot, Antonio Lorca-Cámara, Valeria Zampini, Florence Bui, Christophe Tourain, Noam Badt, Ori Katz, Valentina Emiliani
Journal: Neuron (2022)
Dually innervated dendritic spines develop in the absence of excitatory activity and resist plasticity through tonic inhibitory crosstalk
Authors: Mason S. Kleinjan, William C. Buchta, Roberto Ogelman, In-Wook Hwang, Masaaki Kuwajima, Dusten D. Hubbard, Dean J. Kareemo, Olga Prikhodko, Samantha L. Olah, Luis E. Gomez Wulschner, Wickliffe C. Abraham, Santos J. Franco, Kristen M. Harris, Won Chan Oh, Matthew J. Kennedy
Journal: Neuron (2022)

Dendritic spines can be directly connected to both inhibitory and excitatory presynaptic terminals, resulting in nanometer-scale proximity of opposing synaptic functions. While dually innervated spines (DiSs) are observed throughout the central nervous system, their developmental timeline and functional properties remain uncharacterized. Here we used a combination of serial section electron microscopy, live imaging, and local synapse activity manipulations to investigate DiS development and function in rodent hippocampus. Dual innervation occurred early in development, even on spines where the excitatory input was locally silenced. Synaptic NMDA receptor currents were selectively reduced at DiSs through tonic GABA
Policy implementation and priorities to create healthy food environments using the Healthy Food Environment Policy Index (Food-EPI): A pooled level analysis across eleven European countries
Authors: Elisa Pineda, Maartje P. Poelman, Anu Aaspõllu, Margarida Bica, Cristina Bouzas, Elena Carrano, Pilar De Miguel-Etayo, Sanne Djojosoeparto, Mojca Gabrijelčič Blenkuš, Pedro Graca, Karin Geffert, Antje Hebestreit, Anni Helldan, Sigrun Henjum, Camilla Sanne Huseby, Maria João Gregório, Carlijn Kamphuis, Tiina Laatikainen, Anne Lene Løvhaug, Clarissa Leydon, Aleksandra Luszczynska, Päivi Mäki, J. Alfredo Martínez, Susanna Raulio, Piotr Romaniuk, Gun Roos, Clara Salvador, Franco Sassi, Marco Silano, Ingrid Sotlar, Maria Lucia Specchia, Miguel Telo de Arriaga, Laura Terragni, Liv Elin Torheim, Josep A. Tur, Peter von Philipsborn, Janas M. Harrington, Stefanie Vandevijvere
Journal: The Lancet Regional Health - Europe (2022)

Food environments have been recognised as highly influential on population diets. Government policies have great potential to create healthy food environments to promote healthy diets. This study aimed to evaluate food environment policy implementation in European countries and identify priority actions for governments to create healthy food environments.The Healthy Food Environment Policy Index (Food-EPI) was used to evaluate the level of food environment policy and infrastructure support implementation in Estonia, Finland, Germany, Ireland, Italy, the Netherlands, Norway, Poland, Portugal, Slovenia, and Spain in 2019-2021. Evidence of implementation of food environment policies was compiled in each country and validated by government officials. National experts evaluated the implementation of policies and identified priority recommendations.Finland had the highest proportion (32%, n = 7/22) of policies shaping food environments with a "high" level of implementation. Slovenia and Poland had the highest proportion of policies rated at very low implementation (42%, n = 10/24 and 36%, n = 9/25 respectively). Policies regarding food provision, promotion, retail, funding, monitoring, and health in all policies were identified as the most important gaps across the European countries. Experts recommended immediate action on setting standards for nutrients of concern in processed foods, improvement of school food environments, fruit and vegetable subsidies, unhealthy food and beverage taxation, and restrictions on unhealthy food marketing to children.Immediate implementation of policies and infrastructure support that prioritize action towards healthy food environments is urgently required to tackle the burden of obesity and diet-related non-communicable diseases in Europe.This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 774548 and from the Joint Programming Initiative "A Healthy Diet for a Healthy Life".
Afucosylation of HLA-specific IgG1 as a potential predictor of antibody pathogenicity in kidney transplantation
Authors: Pranay Bharadwaj, Sweta Shrestha, Tamas Pongracz, Catalano Concetta, Shilpee Sharma, Alain Le Moine, Noortje de Haan, Naoka Murakami, Leonardo V. Riella, Vanda Holovska, Manfred Wuhrer, Arnaud Marchant, Margaret E. Ackerman
Journal: Cell Reports Medicine (2022)

Antibody-mediated rejection (AMR) is the leading cause of graft failure. While donor-specific antibodies (DSAs) are associated with a higher risk of AMR, not all patients with DSAs develop rejection, suggesting that the characteristics of alloantibodies determining their pathogenicity remain undefined. Using human leukocyte antigen (HLA)-A2-specific antibodies as a model, we apply systems serology tools to investigate qualitative features of immunoglobulin G (IgG) alloantibodies including Fc-glycosylation patterns and FcγR-binding properties. Levels of afucosylated anti-A2 antibodies are elevated in seropositive patients, especially those with AMR, suggesting potential cytotoxicity via FcγRIII-mediated mechanisms. Afucosylation of both glycoengineered monoclonal and naturally glycovariant polyclonal serum IgG specific to HLA-A2 drives potentiated binding to, slower dissociation from, and enhanced signaling through FcγRIII, a receptor widely expressed on innate effector cells, and greater cytotoxicity against HLA-A2+ cells mediated by natural killer (NK) cells. Collectively, these results suggest that afucosylated DSA may be a biomarker of AMR and contribute to pathogenesis.
Genome-scale CRISPR screening in a single mouse liver
Authors: Heather R. Keys, Kristin A. Knouse
Journal: Cell Genomics (2022)

A complete understanding of the genetic determinants underlying mammalian physiology and disease is limited by the capacity for high-throughput genetic dissection in the living organism. Genome-wide CRISPR screening is a powerful method for uncovering the genetic regulation of cellular processes, but the need to stably deliver single guide RNAs to millions of cells has largely restricted its implementation to ex vivo systems. There thus remains a need for accessible high-throughput functional genomics in vivo. Here, we establish genome-wide screening in the liver of a single mouse and use this approach to uncover regulation of hepatocyte fitness. We uncover pathways not identified in cell culture screens, underscoring the power of genetic dissection in the organism. The approach we developed is accessible, scalable, and adaptable to diverse phenotypes and applications. We have hereby established a foundation for high-throughput functional genomics in a living mammal, enabling comprehensive investigation of physiology and disease.
Identification of PCSK9-like human gene knockouts using metabolomics, proteomics, and whole-genome sequencing in a consanguineous population
Authors: Aziz Belkadi, Gaurav Thareja, Fatemeh Abbaszadeh, Ramin Badii, Eric Fauman, Omar M.E. Albagha, Karsten Suhre
Journal: Cell Genomics (2022)

Natural human knockouts of genes associated with desirable outcomes, such as PCSK9 with low levels of LDL-cholesterol, can lead to the discovery of new drug targets and treatments. Rare loss-of-function variants are more likely to be found in the homozygous state in consanguineous populations, and deep molecular phenotyping of blood samples from homozygous carriers can help to discriminate between silent and functional variants. Here, we combined whole-genome sequencing with proteomics and metabolomics for 2,935 individuals from the Qatar Biobank (QBB) to evaluate the power of this approach for finding genes of clinical and pharmaceutical interest. As proof-of-concept, we identified a homozygous carrier of a very rare PCSK9 variant with extremely low circulating PCSK9 levels and low LDL. Our study demonstrates that the chances of finding such variants are about 168 times higher in QBB compared with GnomAD and emphasizes the potential of consanguineous populations for drug discovery.
Tissue-specific transcriptional profiles and heterogeneity of natural killer cells and group 1 innate lymphoid cells
Authors: Noella Lopes, Justine Galluso, Bertrand Escalière, Sabrina Carpentier, Yann M. Kerdiles, Eric Vivier
Journal: Cell Reports Medicine (2022)

Natural killer (NK) cells and type 1 innate lymphoid cells (ILC1s) are populations of non-T, non-B lymphocytes in peripheral tissues. Although NK and ILC1 subsets have been described, their identification and characteristics remain unclear. We performed single-cell RNA sequencing and CITE-seq to explore NK and ILC1 heterogeneity between tissues. We observed that although NK1 and NK2 subsets are conserved in spleen and liver, ILC1s are heterogeneous across tissues. We identified sets of genes expressed by related subsets or characterizing unique ILC1 populations in each organ. The syndecan-4 appeared as a marker discriminating murine ILC1 from NK cells across organs. Finally, we revealed that the expressions of EOMES, GZMA, IRF8, JAK1, NKG7, PLEK, PRF1, and ZEB2 define NK cells and that IL7R, LTB, and RGS1 differentiate ILC1s from NK cells in mice and humans. Our data constitute an important resource to improve our understanding of NK-ILC1 origin, phenotype, and biology.
Outcomes by Cardiac Stage in Patients With Newly Diagnosed AL Amyloidosis
Authors: Monique C. Minnema, Angela Dispenzieri, Giampaolo Merlini, Raymond L. Comenzo, Efstathios Kastritis, Ashutosh D. Wechalekar, Martha Grogan, Ronald Witteles, Frederick L. Ruberg, Mathew S. Maurer, NamPhuong Tran, Xiang Qin, Sandra Y. Vasey, Brendan M. Weiss, Jessica Vermeulen, Arnaud Jaccard
Journal: JACC CardioOncology (2022)

Patients with amyloid light chain amyloidosis and severe cardiac dysfunction have a poor prognosis. Treatment options that induce rapid and deep hematologic and organ responses, irrespective of cardiac involvement, are needed.The aim of this study was to evaluate the impact of baseline cardiac stage on efficacy and safety outcomes in the phase 3 ANDROMEDA trial.Rates of overall complete hematologic response and cardiac and renal response at 6 months and median major organ deterioration-progression-free survival and major organ deterioration-event-free survival were compared across cardiac stages (I, II, or IIIA) and treatments (daratumumab, bortezomib, cyclophosphamide, and dexamethasone [D-VCd] or bortezomib, cyclophosphamide, and dexamethasone [VCd]). Rates of adverse events (AEs) were summarized for patients with and without baseline cardiac involvement and by cardiac stage.Median follow-up duration was 15.7 months. The proportions of stage I, II, and IIIA patients were 23.2%, 40.2%, and 36.6%. Across cardiac stages, hematologic and organ response rates were higher and major organ deterioration-progression-free survival and major organ deterioration-event-free survival were longer with D-VCd than VCd. AE rates were similar between treatments and by cardiac stage; serious AE rates were higher in patients with cardiac involvement and increased with increasing cardiac stage. The incidence of cardiac events was numerically greater with D-VCd vs VCd, but the rate of grade 3 or 4 events was similar. The exposure-adjusted incidence rate for cardiac events was lower with D-VCd than VCd (median exposure 13.4 and 5.3 months, respectively).These findings demonstrate the efficacy of D-VCd over VCd in patients with newly diagnosed amyloid light chain amyloidosis across cardiac stages, thus supporting its use in patients with cardiac involvement. (NCT03201965).
Cardioprotection Using Strain-Guided Management of Potentially Cardiotoxic Cancer Therapy
Authors: Tomoko Negishi, Paaladinesh Thavendiranathan, Martin Penicka, Julie Lemieux, Klaus Murbraech, Sakiko Miyazaki, Mitra Shirazi, Ciro Santoro, Goo-Yeong Cho, Bogdan A. Popescu, Wojciech Kosmala, Ben Costello, Andre la Gerche, Phil Mottram, Liza Thomas, Stephanie Seldrum, Krassimira Hristova, Manish Bansal, Koji Kurosawa, Nobuaki Fukuda, Hirotsugu Yamada, Masaki Izumo, Kazuko Tajiri, Maciej Sinski, Dragos Vinereanu, Evgeny Shkolnik, Jose Banchs, Shelby Kutty, Kazuaki Negishi, Thomas H. Marwick
Journal: JACC. Cardiovascular imaging (2022)
AL Amyloidosis for Cardiologists
Authors: Ashutosh D. Wechalekar, Marianna Fontana, C. Cristina Quarta, Michaela Liedtke
Journal: JACC CardioOncology (2022)

Amyloid light chain (AL) amyloidosis is a rare, debilitating, often fatal disease. Symptoms of cardiomyopathy are common presenting features, and patients often are referred to cardiologists. Cardiac amyloid infiltration is the leading predictor of death. However, the variable presentation and perceived rarity of the disease frequently lead to delay in suspecting amyloidosis as a cause of heart failure, leading to misdiagnoses and a marked delay in diagnosis, with devastating consequences for the patient. A median time from symptom onset to correct diagnosis of about 2 years is often too long when median survival from diagnosis for patients with AL amyloidosis and cardiomyopathy is 4 months to 2 years. The authors highlight the challenges to diagnosis, identify gaps in the current knowledge, and summarize novel treatments on the horizon to raise awareness about the critical need for early recognition of symptoms and diagnosis of AL amyloidosis aimed at accelerating treatment and improving outcomes for patients.
Structural Heart Imaging Survey Highlights
Authors: James C. Lee, Jeffrey B. Geske, Akhil Narang, Omar K. Khalique, Andrew D. Choi, Yee-Ping Sun, João L. Cavalcante, Duane S. Pinto, Sameer A. Gafoor, Dinesh H. Jagasia, Marcelo F. DiCarli, Todd C. Villines, Stephen H. Little, Rebecca T. Hahn, Dee Dee Wang
Journal: JACC. Cardiovascular imaging (2022)
Pulmonary Hypertension by Catheterization Is More Accurately Detected by Cardiovascular Magnetic Resonance 4D-Flow Than Echocardiography
Authors: João G. Ramos, Björn Wieslander, Alexander Fyrdahl, Gert Reiter, Ursula Reiter, Ning Jin, Viktoria Skott, Michael Melin, Patrik Sundblad, Andreas Sigfridsson, Martin Ugander
Journal: JACC. Cardiovascular imaging (2022)
Prognosis of Transthyretin Cardiac Amyloidosis Without Heart Failure Symptoms
Authors: Esther Gonzalez-Lopez, Luis Escobar-Lopez, Laura Obici, Giulia Saturi, Mélanie Bezard, Sunil E. Saith, Omar F. AbouEzzeddine, Roberta Mussinelli, Christian Gagliardi, Mounira Kharoubi, Jan M. Griffin, Angela Dispenzieri, Silvia Vilches, Stefano Perlini, Simone Longhi, Silvia Oghina, Adrian Rivas, Martha Grogan, Mathew S. Maurer, Thibaud Damy, Giovanni Palladini, Claudio Rapezzi, Pablo Garcia-Pavia
Journal: JACC CardioOncology (2022)

Transthyretin amyloid cardiomyopathy (ATTR-CM) is increasingly recognized as a treatable cause of heart failure (HF). Advances in diagnosis and therapy have increased the number of patients diagnosed at early stages, but prognostic data on patients without HF symptoms are lacking. Moreover, it is unknown whether asymptomatic patients benefit from early initiation of transthyretin (TTR) stabilizers.The aim of this study was to describe the natural history and prognosis of ATTR-CM in patients without HF symptoms.Clinical characteristics and outcomes of patients with ATTR-CM without HF symptoms were retrospectively collected at 6 international amyloidosis centers.A total of 118 patients (78.8% men, median age 66 years [IQR: 53.8-75 years], 68 [57.6%] with variant transthyretin amyloidosis, mean left ventricular ejection fraction 60.5% ± 9.9%, mean left ventricular wall thickness 15.4 ± 3.1 mm, and 53 [45%] treated with TTR stabilizers at baseline or during follow-up) were included. During a median follow-up period of 3.7 years (IQR: 1-6 years), 38 patients developed HF symptoms (23 New York Heart Association functional class II and 14 functional class III or IV), 32 died, and 2 required cardiac transplantation. Additionally, 20 patients received pacemakers, 13 developed AF, and 1 had a stroke. Overall survival was 96.5% (95% CI: 91%-99%), 90.4% (95% CI: 82%-95%), and 82% (95% CI: 71%-89%) at 1, 3, and 5 years, respectively. Treatment with TTR stabilizers was associated with improved survival (HR: 0.31; 95% CI: 0.12-0.82; P = 0.019) and remained significant after adjusting for sex, age, ATTR-CM type, and estimated glomerular filtration rate (HR: 0.18; 95% CI: 0.06-0.55; P = 0.002).After a median follow-up period of 3.7 years, 1 in 3 patients with asymptomatic ATTR-CM developed HF symptoms, and nearly as many died or required cardiac transplantation. Treatment with TTR stabilizers was associated with improved prognosis.